Prostate cancer is a heterogeneous disease, ranging from asymptomatic to a rapidly fatal metastatic malignancy in men. It is the most commonly diagnosed cancer in men in the US, with approximately 240,000 newly diagnosed patients and over 30,000 cancer deaths each year. Progress in treating human prostate cancer has been hampered by the finding that histologically similar cancers can exhibit widely variant clinical behavior. For example, in some men, the disease progresses slowly with a prolonged natural history while in others, disease progression can be rapid so that local therapy is ineffective. The uncertainty regarding appropriate clinical management of prostate cancer in many patients is related to the fact that similar tumor phenotypes can harbor diverse molecular and genetic changes that can affect prostate cancer development and disease progression.
A variety of clinical models or nomograms have been developed to aid clinicians with pre-treatment risk assessment. For example, since 1988, the routine use of serum prostate-specific antigen (PSA) testing in men at risk for prostate cancer has led to more favorable disease characteristics at presentation (mainly more localized disease) and more effective treatment. Several investigators have used these clinical parameters to stratify patients into risk groups (low, intermediate, high) and to predict clinical outcomes (Nomograms). Despite these useful parameters, approximately 20-30% of patients with low to intermediate-risk prostate cancer fail standard treatment as evidenced by a rising serum PSA following definitive therapy. A better understanding of the molecular abnormalities that define tumors from patients who are at high risk for relapse is needed to help stratify patients into biologically defined groups with similar risk factors.
Three well-defined predictors of disease extent and outcome following treatment are known in newly diagnosed patients. These factors are (1) clinical tumor stage (T1-T4) by digital rectal examination, (2) Gleason score of the diagnostic biopsy specimen and (3) serum PSA levels. However, each of these factors alone has not proven definitive in predicting disease extent and outcome for an individual patient. Clinical staging by digital rectal examination may underestimate the presence of extracapsular disease extension in 30-50% of patients. Although, Gleason score on biopsies may be helpful in predicting pathologic stage and outcome following treatment at either end of the spectrum (i.e., Gleason 2-4 or Gleason 8-10 tumors), it is less helpful for the majority of patients who present with “intermediate” Gleason 5-7 disease. As risk assessment methods for patients newly diagnosed with prostate cancer continue to evolve, newer tools, such as genetic or molecular determinants are expected to be able to better predict the behavior of an individual tumor.
Surgical treatment is usually reserved for prostate cancer patients in good general health with tumor confined to the prostate gland (Stage I and Stage II). However, a fraction of these patients will fail the treatment as judged by chemical failure (elevation of PSA level) or development of metastasis (commonly in lymph nodes and bone). Urgent need also exists for methods that can stratify patients with clinically-low risk disease into active surveillance vs. definitive therapy. Currently, a significant proportion of patients face uncertainty with respect to their decision to undergo surgery or to choose active surveillance as well as their prognosis after surgery. Existing methods for assessing clinical risk include the various pathological (e.g., tumor stage), histological (e.g., Gleason's score), molecular biomarkers (e.g., PSA), or more complex methods which combine those markers in a nomogram (e.g. Kattan, et al., “Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer,” J Clin Oncol, 17:1499-1507 (1999)). However, using these methods for future risk assessment is unreliable in ˜20 to 30% of prostate cancer patients with low or intermediate stage disease. Routine PSA testing has increased the pool of patients with early disease and, with this, the need for more reliable stratification. The ability to identify, or predict, a post-surgery patient as likely to encounter PSA failure, recurrence of the prostate cancer, and/or development of metastasis, would provide multiple benefits to the patient.
Currently, no single diagnostic test is capable of predicting with high certainty clinical progression of the disease. Although detection of prostate cancer is routinely achieved with physical examination and/or clinical tests such as serum PSA, a definitive diagnosis of prostate cancer requires confirmation by biopsy and histopathological evaluation.
In patients with clinically extreme disease (very early or very advanced), currently available prognostic approaches predict more reliably the probability of disease-free survival. Previous studies correlated patient survival time with the extent and spread of the prostatic carcinoma. For example, studies have shown that when the cancer is confined to the prostate gland, median survival in excess of five years can be anticipated. Patients with locally advanced cancer have a much poorer prognosis. Other factors affecting the prognosis of patients with prostate cancer that are useful in making therapeutic decisions include histologic grade of the tumor, patient's age, other medical illnesses, and PSA levels. However, such factors, as mentioned above, are of more limited value in a large proportion of intermediate stage tumors.
Information on any condition of a particular patient and a patient's response to therapeutic or nutritional agents has become an important issue in clinical medicine not only from the aspect of efficiency of medical practice for the health care industry but for improved outcomes and benefits for patients. The clinical course of prostate cancer can be unpredictable and the prognostic significance of the current diagnostic measures remains limited.
It is now recognized that prostate cancer exhibits altered gene expression changes in hundreds of genes, many of which genes directly influence outcome. Bibikova, M., et al., “Expression signatures that correlated with Gleason score and relapse in prostate cancer,” Genomics, 89(6):666-72 (2007); Henshall, S. M., et al., “Survival analysis of genome-wide gene expression profiles of prostate cancers identifies new prognostic targets of disease relapse,” Cancer Res, 63(14):4196-203 (2003); Quinn, D. I., et al., “Molecular markers of prostate cancer outcome,” Eur J Cancer, 41(6):858-87 (2005); Henshall, S. M., et al., “Zinc-alpha2-glycoprotein expression as a predictor of metastatic prostate cancer following radical prostatectomy,”J Natl Cancer Inst, 98(19):1420-4 (2006); Stephenson, R. A, et al., “Metastatic model for human prostate cancer using orthotopic implantation in nude mice,” Journal of the National Cancer Inst, 84: 951-7 (1992); Stuart, R. O., et al., “In silico dissection of cell-type-associated patterns of gene expression in prostate cancer,” Proc Natl Acad Sci USA, 101(2):615-20 (2004); Richardson, A M., et al., “Global expression analysis of prostate cancer-associated stroma and epithelia,” Diagn Mol Pathol, 16(4):189-97 (2007). See also U.S. patent publications US2010-0009581, US2011-0153534, US2011-0136683, US2011-0251987; US2009-0298082; US2010-0047787; US2011-0236903; US2011-0230361; US2010-0137164; and US2012-0028264. However a recent consensus statement by a panel of prostate SPORE leaders (the Inter-SPORE Prostate Biomarkers Study and NBN Pilot group) has tersely summarized that few or none have proven reliable enough to advance to clinical use (prostatenbnpilot.nci.nih.gov/aboutpilot_ipbs.asp).
Thus, a need exists for large-scale discovery, validation, and clinical application of mRNA biosignatures of disease and for methods of genomic analysis in patients with established clinical prostate cancer to predict disease outcomes, thereby aiding in the diagnosis, in the management of therapy, as well as in the ability to predict the survival time of patients with prostate cancer. The present invention satisfies this need and provides additional advantages.